Posaconazole (CAS Registry Number 171228-49-2; CAS Name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol) is a triazole antifungal drug represented by the structure:

Posaconazole is used, for example, to prevent and/or treat invasive fungal infections caused by Candida species, Mucor species, Aspergillus species, Fusarium species, or Coccidioides species in immunocompromised patients and/or in patients where the disease is refractory to other antifungal agents such as amphothericin B, fluconazole, or itraconazole, and/or in patients who do not tolerate these antifungal agents.
Currently known processes for the preparation of Posaconazole including a cyclization reaction wherefrom the oxo-triazole according to above-shown structure results. In this respect, reference is made to WO 96/33178 A1 and WO 95/17407 A1. Said processes involve the heating of the respective starting material, namely a benzyl-protected starting material, in toluene as solvent in the presence of the strong organic base DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and a suitable molecular sieve with the exclusion of moisture. Long reaction times of at least 36 h are necessary, and a sophisticated temperature-time profile is required. Further, work-up of the obtained product is elaborate and therefore, for commercial-scale production, expensive since numerous washing steps, filtration steps, and further purification steps are needed. Among others, vacuum distillation has to be applied in order to obtain the benzyl-protected target compound. Since the benzyl protecting group has to be separated by a palladium-catalysed hydrogenation, contamination of the target compound with Pd may pose a problem.
As mentioned above, according to the prior art process, the starting material for said cyclization process is a compound in which the —OH group is benzyl-protected. Using a starting material with a non-protected —OH group is conceivable if silylation agents such as TMS (trimethylsilyl) chloride or BSA (bis-trimethylsilyl acetamide) are added which allow for an in situ protection of the —OH group and simultaneously for an activation of respective carbonyl groups in terms of the cyclization reaction. Cyclization may be further improved if TMS iodide is added. As in the prior art processes discussed above, this improved process has to be carried out with the exclusion of moisture. While the reaction times are considerably improved compared to above-mentioned prior art processes and are, for example, in the range of 16 h, and while the absence of a protecting group is certainly a major advantage over the prior art processes discussed above, there is nevertheless a need for an even more improved process which exhibits advantages with respect the specific nature of the chemical compounds used and/or the reaction parameters such as reaction times and the like. Further, taking into account the tedious purification process of the known prior art processes discussed above, there is also a need for a process which allows for a simplified work-up procedure.